Complex glucosaminic acid salts of the metals of the iron group



Patented-Nov. 15, 1932 UNITED STATES ARTHUR STOLL AND ALBERT HOFMANN, OFBASEL, SWITZERLAND, ASSIGNORS TO FIRM OF GHEMIGAL WORKS FORMERLY SANDOZ,OF BASEL, SWITZERLAND..

PATENT OFFICE COMPLEX eLUcosAmmcAcIn sans or ran META sor THE momv G OUPNo Drawing. A pplication filed November 5, 1931, Serial no; 573,298, andin Germany November 10, 1930.

The present invention relates to the prep-' aration of complexglucosaminic acid salts of the metals of the iron group which possessvaluable therapeutical properties.

It isknown that the derivatives of metals in order that they can be usedin the therapy, must possess some special properties, such' as forexample a small toxicity, a good toleration on injection and asufficient solubility. The first two properties depend on the chem icalconstitution of the compound, which for this purpose must possess aneutral character and in which the metal must be linked in a complexmanner, whereas the solubility in water generally depends on thepresence of an acid group which is neutralized with an alkali metal oron the presence of several hydroxylic groups in the molecule.

It has now been found, that the glucosaminic acid yields such metalsalts, that completely fulfil the above cited requirements. They arevery stable and contain probably a five ring, as shown by the followingfOIIDIl lae, like the heavy metal salts of other amino acids, e.the'copper salt of glycocoll (see P. Pfeifier OrganischeMolekiilverbindungen, 1922, page 176) The capacity for the formation ofcomplex compounds is further increased by the presence of the alcoholichydroxylic groups contained in the molecule of the glucosaminic acid, asit is well known that the polyoxycarboxylic acids such as tartaric acidgive complex metal compounds. The metal compounds of the glucosaminicacid, containing in their molecule besides one amino group severalhydroxylic groups possess a much better stability of the metalcomplex,produce a smaller irritation of the tissues on injection and are muchbetter tolerated, in comparison with metal compounds of the oxyandpolyoxy-carboxylic acids that do not contain an amino group. As comparedto the complex heavy metal salts of the usual aminoacidsv which containno oronly "one hydroxylic group andwhic'h owing to their bad solubilitypresent no interest for therapeutical purposes, the new compounds pre-'pared according to the present process possess quite a sufiicientsolubility for the therapeutical application and may, therefore besuccessfully used.

According to the literature, some normal metal salts. of theglucosaminicacid, such as the copper, zinc and silver salts have 2.1-

ready been prepared for the purpose of characterizing this acid (see E.Fischer & F. Thiemann, Ber. 27, page 144, 1894). But from thispublication it could not at all be foreseen, that the glucosaminic acidwould yield with other metals therapeutically valuable and complexcompounds, for the reason, that the described copper salt isinsoluble-in. water and the silver salt is unstable and is decomposedunder reduction to the metal. 'wm a .For the preparation of the newcompounds several methodsmay be used.

By treating the glucosaminic acid with oxides or hydroxides of themetals the new compounds maybe obtained; The same result is reachedif anequivalent quantity of an organic or an inorganic base is added to asolution containing the glucosaminic acid and the heavy'metalsalt,whereby the metal hydroxide obtained in statu nasc-endi reacts with theglucosami'nic acid. In the case where the sulphates of the heavy metalsare used it islindicated to employ barium hydrox ide, because theprecipitated barium sulphate can easily be separated from the solution;By using the metal chlorides, it is preferable to produce the metalhydroxides by means of an addition of diethylamine or of similar bases,the chlorides of which are soluble in alcohol andmay therefore be easilyseparated from the metal salts of the glucosaminic acid which areinsoluble-therein. 1

i It is further also possible to treat an aqueone solutionoftheglucosaminic acid with a carbonate of a heavy metal, whereby thecarbonate is'dis solvedunder production of 7 carbon dioxide, althoughthe glucosaminic in 20 parts of water is added at 95 salts whichcorrespond to the valency of the metals and which are generally wellcrystal lized, also such compounds of the glucosaminic acid that containtwo, three or several times more of a metal than corresponds to thenormal stochiometric proportion. Such salts are distinguished by a goodsolubility.

The heavy metal salts ofthe glucosaminic acid do not yield with alkalior with other basic compounds a precipitation of the heavy metalhydroxide, but they give the easily soluble double salts of heavy metaland alkali metal or aminosalts of the glucosaminlc acid.

- The new process is illustrated by the following examples, which arenot limitative,

the parts being by weight. Example 1 To a solution of 1 part ofglucosaminic acid C. 1 part of nickel carbonate, whereby carbon dioxideescapes and the solution becomes blue. After 10 minutes the solution isseparated from the excess of nickel carbonate by filtration and the hotfiltrate obtained is diluted with 10 parts of hot alcohol of Thecrystallization of nickel glucosaminate begins immediately. Pale bluecrystals of the. composition (C H O N) Ni.containing 12.96%

* of Ni (theor. 13.1%) areobtained. By dissolving one molecule of nickelglucosaminate in one molecule of a 2-n-sodium hydroxide solution a darkblue solution is obtained from which the nickel-sodiumgluoosaminate ofthe composition (C H O N) Ni] Na is precipitated by means of absolutealcohol.

By dissolving one molecule of, nickelglucosaminate in 2 molecules ofsodium hydroxide an intensively green colored nickel glucosaminate isobtained. 2 1

Ewample 2 To a solution of 1 part of glucosaminic acid in 20 parts ofwater is added at 95 C. one part of cobalt carbonate, whereby carbondioxide escapes and the solution becomes the solution is filtered andthe filtrate introduced into parts ofabsolute alcohol. The very easilysoluble cobalt glucosaminate is obtained in form of a wine-red powder ofthe composition (C H O N) Co. 65

By working as described in Examplel the respectivecobalt-alkalimetalglucosaminates may be prepared.

Example 3 A concentrated aqueous solution containing one molecule ofglucosaminic acid and one molecule of ferric chloride is treated with 3molecules of diethylamine, whereby the solution becomes colored in adeep brown-red shade. By introducing this solution into absolute alcoholthe iron glucosaminate is precipitated in form of rusty-brown flocks.The product thus obtained contains generally traces of chlorine; Inorder to separate them, the salt is again dissolved in a small quantityof water and reprecipitated by introdu-cing the aqueous solution intoalcohol containing a small amount of di-ethylamine and eventually acertain quantity of ether. A rusty-brown powder of the composition C H ONFe is obtainedin this manner. It contains 23.1% of Fe (theor. 22.5%).

By replacing the ferric chloride by a salt of the bivalent iron, asimilar complex salt is obtained. Its aqueous solutions are dark green,but change the color on oxidation by air.

Similar salts may also be prepared from salts of the bivalent andtrivalent manganese salts. They are also soluble in water with a browncoloration and yield stable aqueous solutions. 7

What we claim is:

The complex glucosaminic acid salts of the iron group, prepared byinteraction of the glucosaminic acid with salts of the metalsof the irongroup, which constitute in dry state nonhygroscopic powders, soluble inwater, yielding stable solutions and which give with basic compoundseasily soluble salts;

In witness whereof we have hereunto signed our names this 27th day ofOctober,

ARTHUR STOLL. ALBERT HOFMANN.

. colored to deep wine-red. After 30 minutes

